1. Field of the Invention
The invention relates to methods for enhancing the complexation of a heterocyclic drug with cyclodextrin and to methods for enhancing the availability of a heterocyclic drug following administration of a cyclodextrin-drug complex.
2. Background Art
Cyclodextrins are a group of structurally related saccharides which are formed by enzymatic cyclization of starch by a group of amylases termed glycosyltransferases. Cyclodextrins are cyclic oligosaccharides, consisting of (xcex1-1,4)-linked xcex1-D-glucopyranose units, with a somewhat lipophilic central cavity and a hydrophilic outer surface. The most common naturally occurring cyclodextrins are xcex1-cyclodextrin, xcex2-cyclodextrin and xcex3-cyclodextrin consisting of 6, 7 and 8 glucopyranose units, respectively. Of these three derivatives, xcex2-cyclodextrin appears to be the most useful pharmaceutical complexing agent due to its cavity size, availability, low cost and other properties.
The natural cyclodextrins, in particular xcex2-cyclodextrin, have limited aqueous solubility and their complex formation with lipophilic drugs often results in precipitation of solid drug-cyclodextrin complexes. Thus, the solubility of xcex2-cyclodextrin in water is only about 18.5 mg/ml at room temperature. This low aqueous solubility is, at least partly, associated with strong intramolecular hydrogen bonding in the cyclodextrin crystal lattice. Substitution of any of the hydrogen bond-forming hydroxyl groups, even by hydrophobic moieties such as methoxy groups, will increase the aqueous solubility of xcex2-cyclodextrin. In addition, since these manipulations frequently produce large numbers of isomeric products, chemical modification can transform the crystalline cyclodextrins into amorphous mixtures increasing their aqueous solubility.
Cyclodextrin derivatives of current pharmaceutical interest include the hydroxypropyl derivatives of xcex1-, xcex2- and xcex3-cyclodextrin, sulfoalkylether cyclodextrins such as sulfobutylether xcex2-cyclodextrin, alkylated cyclodextrins such as the randomly methylated xcex2-cyclodextrin, and various branched cyclodextrins such as glucosyl- and maltosyl-xcex2-cyclodextrin (T. Loftsson and M. E. Brewster, xe2x80x9cCyclodextrins as pharmaceutical excipientsxe2x80x9d, Pharm. Technol. Eur., 9(5), 26-34 (1997); T. Loftsson and M. E. Brewster, xe2x80x9cPharmaceutical applications of cyclodextrins. I. Drug solubilization and stabilizationxe2x80x9d, J. Pharm. Sci. 85(10), 1017-1025 (1996); R. A. Rajewski and V. J. Stella, xe2x80x9cPharmaceutical applications of cyclodextrins. 2. In vivo drug deliveryxe2x80x9d, J. Pharm. Sci. 85(11), 1142-1169 (1996); T. Irie and K. Uekama, xe2x80x9cPharmaceutical applications of cyclodextrins. 3. Toxicological issues and safety evaluationxe2x80x9d, J. Pharm. Sci., 86(2), 147-162 (1997); V. J. Stella and R. A. Rajewski, xe2x80x9cCyclodextrins: their future in drug formulation and deliveryxe2x80x9d, Pharm. Res., 14(5), 556-567 (1997); T. Loftsson, xe2x80x9cIncreasing the cyclodextrin complexation of drugs and drug bioavailability through addition of water-soluble polymersxe2x80x9d, Pharmazie, 53, 733-740 (1998)).
In aqueous solutions, cyclodextrins form complexes with many drugs through a process in which the water molecules located in the central cavity are replaced by either the whole drug molecule, or more frequently, by some lipophilic portion of the drug structure. Once included in the cyclodextrin cavity, the drug molecules may be dissociated through complex dilution, by replacement of the included drug by some other suitable molecule (such as dietary lipids or bile salts in the GI tract) or, if the complex is located in close approximation to a lipophilic biological membrane (such as the mucosal membrane of the GI tract), the drug may be transferred to the matrix for which it has the highest affinity. Importantly, since no covalent bonds are formed or broken during the drug-cyclodextrin complex formation, the complexes are in dynamic equilibrium with free drug and cyclodextrin molecules (R. A. Rajewski and V. J. Stella, xe2x80x9cPharmaceutical applications of cyclodextrins. 2. In vivo drug deliveryxe2x80x9d, J. Pharm. Sci. 85(11), 1142-1169 (1996)).
Various methods have been applied to the preparation of drug-cyclodextrin complexes (T. Loftsson and M. E. Brewster, xe2x80x9cPharmaceutical applications of cyclodextrins. I. Drug solubilization and stabilizationxe2x80x9d, J. Pharm. Sci. 85(10), 1017-1025 (1996); T. Loftsson and M. E. Brewster, xe2x80x9cCyclodextrins as pharmaceutical excipientsxe2x80x9d, Pharm. Technol. Eur., 9(5), 26-34 (1997)). In solution, the complexes are usually prepared by addition of an excess amount of the drug to an aqueous cyclodextrin solution. The suspension formed is equilibrated (for periods of up to one week at the desired temperature) and then filtered or centrifuged to form a clear drug-cyclodextrin complex solution. Since the rate determining step in complex formation is often the phase to phase transition of the drug molecule, it is sometimes possible to shorten this process by formation of supersaturated solutions through sonication followed by precipitation. For preparation of the solid complexes, the water is removed from the aqueous drug-cyclodextrin solutions by evaporation or sublimation, e.g. spray-drying or freeze-drying. Other methods can also be applied to prepare solid drug-cyclodextrin complexes including kneading methods, co-precipitation, neutralization and grinding techniques. In the kneading method, the drug is added to an aqueous slurry of a poorly water-soluble cyclodextrin such as xcex2-cyclodextrin. The mixture is thoroughly mixed, often at elevated temperatures, to yield a paste which is then dried. This technique can frequently be modified so that it can be accomplished in a single step with the aid of commercially available mixers which can be operated at temperatures over 100xc2x0 C. and under vacuum. The kneading method is a cost-effective means for preparing solid cyclodextrin complexes of poorly water-soluble drugs. Co-precipitation of a cyclodextrin complex through addition of organic solvent is also possible. Unfortunately, the organic solvents used as precipitants can interfere with complexation which makes this approach less attractive than the kneading method. However, we have discovered that some organic solvents under some specific conditions, e.g. 10% (v/v) aqueous acetic acid solution, can enhance the complexation. Solid complexes of ionizable drugs can sometimes be prepared by the neutralization method wherein the drug is dissolved in an acidic (for basic drugs) or basic (for acidic drugs) aqueous cyclodextrin solution. The solubility of the drug is then lowered through appropriate pH adjustments (i.e. formation of the unionized drug) to force the complex out of solution. Finally, solid drug-cyclodextrin complexes can be formed by the grinding of a physical mixture of the drug and cyclodextrin and then heating the mixture in a sealed container to 60 to 90xc2x0 C.
For a variety of reasons including cost, production capabilities and toxicology, the amounts of cyclodextrin which can be used in most drug formulations is limited (T. Loftsson and M. E. Brewster, xe2x80x9cCyclodextrins as pharmaceutical excipientsxe2x80x9d, Pharm. Technol. Eur., 9(5), 26-34 (1997); T. Loftsson, xe2x80x9cIncreasing the cyclodextrin complexation of drugs and drug bioavailability through addition of water-soluble polymersxe2x80x9d, Pharmazie, 53, 733-740 (1998)).
If one drug molecule (D) forms a complex with one cyclodextrin molecule (CD), then the complexation efficiency ([D-CD]/[CD]) will be equal to the intrinsic solubility of the drug (S0) times the stability constant of the drug-cyclodextrin complex (KC). In aqueous cyclodextrin solutions saturated with drug, the concentration of free drug ([D]) is approximately equal to S0. Thus, increased complexation efficiency can be obtained by either increasing S0 or by increasing KC or by increasing both simultaneously. Addition of organic solvents, such as ethanol, to the aqueous complexation media can result in enhanced complexation efficiency through increase in S0. Drug ionization can increase the complexation efficiency through increase in S0. Addition of certain low molecular weight acids, such as acetic, citric, malic, or tartaric acid, to aqueous complexation media can enhance cyclodextrin solubilization of basic drugs through increase in S0 (i.e. salt formation, pH changes and lowering melting point) and/or increase in the apparent KC. Water-soluble polymers can increase the complexation efficiency through increase in the apparent KC. Furthermore, it is often possible to enhance cyclodextrin complexation even further by using several different methods simultaneously to enhance the cyclodextrin complexation. Pharmaceutical applications of these and other methods have been reviewed (See T. Loftsson, xe2x80x9cIncreasing the cyclodextrin complexation of drugs and drug bioavailability through addition of water-soluble polymersxe2x80x9d, Pharmazie, 53, 733-740 (1988); T. Loftsson and M. E. Brewster, xe2x80x9cCyclodextrins as pharmaceutical excipientsxe2x80x9d, Pharm. Technol. Eur., 9(5), 26-34 (1997); T. Loftsson and M. E. Brewster, xe2x80x9cPharmaceutical applications of cyclodextrins. I. Drug solubilization and stabilizationxe2x80x9d, J. Pharm. Sci. 85(10), 1017-1025 (1996)).
The cyclodextrin molecules are relatively large (molecular weight ranging from almost 1000 to over 1500), with a hydrated outer surface, and under normal conditions, cyclodextrin molecules will only permeate biological membranes with considerable difficulty (R. A. Rajewski and V. J. Stella, xe2x80x9cPharmaceutical applications of cyclodextrins. 2. In vivo drug deliveryxe2x80x9d, J. Pharm. Sci. 85(11), 1142-1168 (1996); T. Irie and K. Uekama, xe2x80x9cPharmaceutical applications of cyclodextrins. 3. Toxicological issues and safety evaluationxe2x80x9d, J. Pharm. Sci. 86(2), 147-162 (1997); K.-H. Frxc3x6mming and J. Szejtli, Cyclodextrins in pharmacy, Kluwer Academic Publishers, Dordrecht, The Netherlands, 1994; T. Loftsson and J. H. Ólafsson, xe2x80x9cCyclodextrins: new drug delivery systems in dermatologyxe2x80x9d, Int. J. Dermatol., 37, 241-246 (1998); T. Loftsson and E. Stefxc3xa1nsson, xe2x80x9cEffect of cyclodextrins on topical drug delivery to the eyexe2x80x9d, Drug Dev. Ind. Pharm. 23(5), 473-481 (1997)). It is generally recognized that cyclodextrins act as true carriers by keeping the hydrophobic drug molecules in solution and deliver them to the surface of the biological membrane, e.g. skin, mucosa or the eye cornea, where they partition into the membrane. The relatively lipophilic membrane has low affinity for the hydrophilic cyclodextrin molecules and therefore they remain in the aqueous membrane exterior, e.g. the aqueous vehicle system, salvia or the tear fluid. Conventional penetration enhancers, such as alcohols and fatty acids, disrupt the lipid layers of the biological barrier. Cyclodextrins, on the other hand, act as penetration enhancers by increasing drug availability at the surface of the biological barrier. Furthermore, addition of water-soluble polymer, such as polyvinylpyrrolidone, apparently increase even further the availability of the drug molecules at the surface of the biological membrane resulting in enhanced drug bioavailability (T. Loftsson, xe2x80x9cIncreasing the cyclodextrin complexation of drugs and drug bioavailability through addition of water-soluble polymersxe2x80x9d, Pharmazie, 53, 733-740 (1998); T. Loftsson, M. Mxc3xa1sson and E. Stefxc3xa1nsson, xe2x80x9cCyclodextrins as Permeation enhancersxe2x80x9d, Proceedings of the 17th Pharmaceutical Technology Conference and Exhibition, Volume 2, Dublin, Mar. 24-26, 1998, pp. 313-324).
It is possible to enhance the cyclodextrin (CD) complexation efficacy, or efficiency, of drugs (D), and other xe2x80x9cguestxe2x80x9d molecules, by either increasing the apparent stability constant (KC) of the drug-cyclodextrin complex (D-CD) or increasing the apparent intrinsic solubility (S0) of the drug. For example, KC can be increased by addition of water-soluble polymers to the aqueous complexation media and S0 can be increased by ionization of the drug molecule, as described previously. However, increased complexation efficiency by itself does not necessarily result in increased drug availability in the aqueous complexation media or increased drug availability from solid drug-cyclodextrin complexes. On the other hand, if the drug-cyclodextrin complexes are prepared under conditions which ensure enhanced complexation and if the complexation efficiency decreases upon administration, then enhanced drug availability will be observed. Thus, the present invention involves: i) enhancement of the complexation efficiency and ii) reduction of the complexation efficiency after administration. For example, it is possible to enhance the complexation efficiency of many ionizable drugs by preparing the complexes at a pH where the drug is ionized but obtain decreased efficiency upon administration due to pH changes and consequent decreased ionization. One example of such a drug is phenytoin (pKa 8.1). Its solubility in water at room temperature (25xc2x0 C.) is only 18 xcexcg/ml at pH 5 and 32 xcexcg/ml at pH 8 (P. A. Schwartz, C. T. Rhodes and J. W. Cooper, xe2x80x9cSolubility and ionisation characters of phenytoinxe2x80x9d, J. Pharm. Sci., 66, 994-997 (1977)). Addition of 25% (w/v) 2-hydroxypropyl-xcex2-cyclodextrin to the aqueous solutions increases the solubility of phenytoin to 5.0 mg/ml at pH 5 and 6.4 mg/ml at pH 8, which is 280- and 200-fold solubility enhancement, respectively. Although the apparent stability constant (KC) of the phenytoin-cyclodextrin complex is much larger for the drug in the unionized form than for the anionic form, it is possible to obtain much higher total solubility by increasing the apparent intrinsic solubility (S0) of the drug (T. Loftsson and N. Bodor, xe2x80x9cEffects of 2-hydroxypropyl-xcex2-cyclodextrin on the aqueous solubility of drugs and transdermal delivery of 17xcex2-estradiolxe2x80x9d, Acta Pharm. Nord., 1, 185-194 (1989)). However, if the pH 8.0 solution was placed in an environment which would decrease the pH from 8 to 5 (e.g. topical application to the skin), then a supersaturated solution would be formed which would result in enhanced drug availability (e.g. it would result in enhanced transdermal drug delivery). Other means to enhance S0 include reversible derivation (e.g. prodrug formation) of the guest molecule and addition of certain low molecular weight acids. The value of KC can, for example, be increased by addition of certain low molecular weight acids, by addition of water-soluble polymers to the aqueous complexation media or by using mixed solvent systems such as aqueous 10% (v/v) acetic acid. For example, addition of the polymers and heating in an autoclave (to 120-140xc2x0 C. for 20-40 minutes) does not only increase the complexation but it has also been shown to enhance transdermal and transcorneal drug delivery (T. Loftsson and A. M. Sigurdardottir, xe2x80x9cCyclodextrins as skin penetration enhancersxe2x80x9d, in J. Szejtli and L. Szente (Eds.) Proceedings of the Eighth International Symposium on Cyclodextrins, Kluwer Academic Publishers, 1996, pp. 403-406; T. Loftsson and E. Stefansson, xe2x80x9cEffect of cyclodextrins on topical drug delivery to the eyexe2x80x9d, Drug Devel. Ind. Pharm., 23(5), 473-481 (1997)). As shown in Table 1 below, it is not enough to add the polymers to the complexation medium. Addition of polymers to the unheated vehicles did not enhance the transdermal delivery of enalaprilat. However, heating the vehicles after addition of the polymers resulted in significant enhancement. The effect of the polymers on the transdermal delivery of enalaprilat can, at least partly, be explained by decreased complexation efficiency (i.e. decrease in KC) at the skin surface.
In one aspect of the present invention there is provided a method for enhancing the complexation efficacy, i.e. efficiency, of a drug with cyclodextrin, said drug having a structure comprising at least one heterocyclic ring having a total of from 4 to 7 ring atoms, of which from 1 to 3 are hetero ring atoms, each of said hetero ring atoms being selected from nitrogen, oxygen and sulfur, said ring being a cyclic imine, enamine, lactone, lactam, thiolactam, anhydride, imide, hemiacetal or hemiketal, said method comprising subjecting said drug to chemically reversible ring-opening so that at least a portion (at least 0.1% by weight) thereof is in ring-opened form, and complexing said drug with cyclodextrin.
In a related aspect of the invention, there is provided a method for enhancing the complexation efficiency of a drug with cyclodextrin, said drug having a structure comprising at least one heterocyclic ring having a total of from 4 to 7 ring atoms, of which from 1 to 3 are hetero ring atoms, each of said hetero ring atoms being selected from nitrogen, oxygen and sulfur, said ring being a cyclic imine, enamine, lactone, lactam, thiolactam, anhydride, imide, hemiacetal or hemiketal, said method comprising complexing said drug with cyclodextrin in an aqueous medium under conditions which effect chemically reversible ring-opening of at least a portion (at least 0.1% by weight) of said drug.
In another aspect of the invention, there is provided a method for enhancing the availability of a drug following administration of a cyclodextrin-drug complex to a warm-blooded animal in need of same, said drug having a structure comprising at least one heterocyclic ring having a total of from 4 to 7 ring atoms of which from 1 to 3 are hetero ring atoms, each of said hetero ring atoms being selected from nitrogen, oxygen and sulfur, said ring being a cyclic imine, enamine, lactone, lactam, thiolactam, anhydride, imine, hemiacetal or hemiketal, said method comprising complexing said drug with cyclodextrin in an aqueous medium under conditions which effect chemically reversible ring-opening of at least a portion (at least 0.1% by weight) of said drug to enhance the complexation efficiency, followed by administering the cyclodextrin-drug complex thus obtained to said animal under conditions which reduce the complexation efficiency.
In still another aspect, the present invention provides a method for enhancing the availability of a basic drug (i.e. a proton acceptor) following administration of a cyclodextrin-drug complex to a warm-blooded animal in need of same, said basic drug having a structure comprising at least one heterocyclic ring having a total of from 4 to 7 ring atoms, of which from 1 to 3 are hetero ring atoms, each of said hetero ring atoms being selected from nitrogen, oxygen and sulfur, said ring being a cyclic imine, enamine, lactone, lactam, thiolactam, anhydride, imide, hemiacetal or hemiketal, said method comprising subjecting said basic drug to complexation in an aqueous medium at a pH level below the pKa+2 value of said basic drug to enhance the complexation efficiency, followed by administering the cyclodextrin-drug complex thus obtained to said animal under conditions which reduce the complexation efficiency.
In yet another aspect, the present invention provides a method for enhancing the availability of an acidic drug following administration of a cyclodextrin-drug complex to a warm-blooded animal in need of same, said acidic drug having a structure comprising at least one heterocyclic ring having a total of 4 to 7 ring atoms, of which from 1 to 3 are hetero ring atoms, each of said hetero ring atoms being selected from nitrogen, oxygen and sulfur, said ring being a cyclic imine, enamine, lactone, lactam, thiolactam, anhydride, imide, hemiacetal or hemiketal, said method comprising subjecting said acidic drug to complexation in an aqueous medium at a pH level above the pKa-2 value of said acidic drug to enhance the complexation efficiency, followed by administering the cyclodextrin-drug complex thus obtained to said animal under conditions which reduce the complexation efficiency.